tbuckley/cabot-search huggingface dataset:
CSIG-03. EGFR LIGAND SHIFTS THE ROLE OF EGFR FROM ONCOGENE TO TUMOR SUPPRESSOR IN EGFR AMPLIFIED GLIOBLASTOMA
Authors: Gao Guo, Ke Gong, Nicole Beckley, Yue Zhang, Xiaoyao Yang, Arifa Nayab, Amyn Habib
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is a devastating cancer largely because of its highly invasive nature. Although pathways that promote GBM invasion have been identified, no pathway that actively suppresses GBM invasion is known and there is no treatment that specifically blocks GBM invasion. EGFR is a prime oncogene and is frequently amplified and mutated in GBM. However multiple clinical trials of EGFR inhibition in GBM have failed. Here, we demonstrate that EGFR ligands activate a tumor suppressor for the EGFR in EGFR-amplified GBMs. Analysis of TCGA data reveals that GBM patients with EGFR amplification and a low level of EGFR ligands have a worse prognosis compared to those with EGFR amplification and a high level of EGFR ligands. We identify the cytoskeletal BAR domain protein BIN3 as a critical suppressor of invasion upregulated by EGFR ligand in EGFR amplified GBMs. BIN3 inhibits a DOCK-7 Rho GTPase pathway, resulting in small hyper-proliferating noninvasive tumors and a better prognosis, while constitutive EGFR wild type or EGFRvIII signaling promotes invasion via activation of a TAB1-TAK1-NF-κB-EMP1 pathway, resulting in large tumors and worse survival in orthotopic models. Consistent with its role as a negative regulator of invasion, BIN3 is deleted in 10% of GBMs and increased expression of BIN3 confers a better prognosis. Thus, increased EGFR ligand shifts the role of EGFR from oncogene to tumor suppressor in EGFR amplified GBMs by suppressing invasion. We identify tofacitinib, a BBB penetrant drug as an upregulator of BIN3 and show that tofacitinib suppresses invasion and prolongs survival in orthotopic models. Our study identifies a new tumor suppressive function of EGFR in GBM and we propose the use of tofacitinib to directly target invasion in EGFR-amplified and EGFR ligand-poor GBMs.
TMET-32. INTRAOPERATIVE MICRODIALYSIS FOR GLIOMA METABOLIC RECONNAISSANCE AND BIOMARKER DISCOVERY
Authors: Cecile Riviere-Cazaux, Lucas Carlstrom, Karishma Rajani, Amanda Munoz-Casabella, Masum Rahman, Terry Burns
Journal: Neuro-Oncology (2022)

Abstract Gliomas are genomically heterogeneous tumors that may harness a convergent and therapeutically targetable set of metabolic pathways. At present, the metabolic landscape of in situ human gliomas remains incompletely characterized, hampering translational progress. To that end, we are leveraging the previously untapped potential of high molecular weight microdialysis to determine the global extracellular metabolic profiles of live human gliomas. Under an investigational device exemption, HMW microdialysis (&amp;lt; 100 kDa) was performed at 2.0 μL/min in an initial discovery cohort of five patients in glioma and adjacent brain during neurosurgical resection; a subsequent cohort of five patients was independently analyzed to critically evaluate results from the discovery group. Untargeted metabolomics via ultra-performance liquid chromatography-tandem mass spectrometry revealed over 300 named metabolites and five drugs from only 20 μL of microdialysate, representing a short and feasible 10 minutes of intraoperative collection time. Enrichment analysis of each patient’s tumor vs. brain ranked extracellular metabolome highlighted marked metabolic convergence within the most aggressive regions of molecular diverse tumors (FDR = 0). Pathway analysis revealed significant enrichment for large neutral amino acid pathways, including valine, leucine, and isoleucine biosynthesis (p=1.6E-9) and degradation (p=0.001) and glycine, serine, and threonine metabolism (p=4.7E-5). Notably, this amino acid signature was not as abundantly present in nonenhancing tumor when compared to enhancing tumor (Average tumor/brain: 1.9x vs. 4.3x, respectively), suggesting upregulation of neutral amino acid transporters in enhancing tumor or delivery from plasma into the CNS via a disrupted BBB. Interestingly, guanidinoacetate (GAA) was our most highly conserved and upregulated metabolite (128.9x in tumor vs. brain). Given its co-production with ornithine, the precursor to protumorigenic polyamines, we posit that GAA may serve as a biomarker of increased ODC activity in live human gliomas. In conclusion, intraoperative HMW microdialysis feasibly offers improved opportunities to perform glioma metabolic biomarker and therapeutic discovery.
INNV-02. MULTIFOCAL, DURABLE AND PATHOLOGICALLY-CONFIRMED BRAIN METASTASIS COMPLETE RESPONSE TO TRASTUZUMAB DERUXTECAN
Authors: Umberto Tosi, Nelson Moss, Bianca Santomasso, Kathryn Beal, Shanu Modi
Journal: Neuro-Oncology (2022)

Abstract Antibody-based conjugates (ADCs) have transformed the treatment of Her2+ breast and other cancers. Unfortunately, the CNS remains a sanctuary site for many such patients in part due to differential activity of macromolecules across the blood-brain and blood-brain tumor barriers. Trastuzumab deruxtecan (T-DXd), a high-payload ADC, was recently found to improve the progression-free survival of Her2+ breast cancer patients compared with prior-generation trastuzumab emtansine, prompting us to evaluate this agent in a woman with CNS-only metastatic disease. T-DXd achieved complete response despite heavy pretreatment. Three persistent (and previously-irradiated) lesions were subsequently biopsy-proven to represent treatment effect. Response was durable through 7 months of treatment, with subsequent recurrence in the setting of treatment holiday; partial response was observed with drug rechallenge. Drug discontinuation was ultimately required due to concern for pulmonary toxicity. Our case suggests T-DXd is active in Her2+ breast cancer brain metastases and supports further prospective evaluation in randomized clinical trials.
EXTH-32. SEQUENTIAL SUNITINIB AND AURANOFIN TREATMENT INDUCEDCYTOTOXICITY THROUGH ROS-MEDIATED MECHANISM IN GLIOBLASTOMA
Authors: Monisha Bagchi, Fatemeh Jamali, Elvis Martinez-jaramillo, Siham Sabri, Bassam Abdulkarim
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) displays aberrant expression of several receptor tyrosine kinases (RTKs) leading to worse prognosis. Despite aggressive treatment including surgery, radiation and the alkylating agent temozolomide (TMZ), GBM tumors counteract deleterious effects of treatment-induced reactive oxygen species (ROS) leading to resistance to standard treatment. Likewise, expression of the DNA repair protein O6-methylguanine-DNA-methyltransferase (MGMT) plays a key role in resistance to TMZ.We previously reported a potential link between MGMT expression and decreased angiogenesis in GBM. The differential expression of MGMT affected response to sunitinib, a multitargeted RTK inhibitor with anti-angiogenic properties FDA-approved in different cancer types. Notably, TMZ-resistant GBM MGMT-positive cells were more vulnerable to sunitinib treatment compared to isogenic MGMT-negative cells. We further provided evidence for a positive relationship between MGMT and the antioxidant enzyme, thioredoxin reductase 1 (TrxR1) in GBM. The TrxR1-targeting drug Auranofin, FDA-approved for rheumatoid arthritis generated ROS and induced more cytotoxic effects in GBM cells displaying low expression of MGMT and TrXR1. We hypothesized that sunitinib-induced anti-proliferative effects might sensitize GBM cells to Auranofin. We showed that MGMT-negative GBM cells, which displayed lower levels of TrxR1, were more vulnerable to Auranofin than MGMT-positive cells. The ROS scavenger N-acetylcysteine (NAC) reverted the cytotoxicity of Auranofin suggesting ROS-mediated cytotoxic effects. Conversely, Sunitinib exhibited ROS-independent anti-proliferative effects in MGMT-positive cells. Remarkably, sequential treatment using sunitinib pre-treatment (2 hours) followed by Auranofin (24 hours) significantly decreased cell viability, clonogenicity, increased ROS, decreased TrXR1 and MGMT expression and sensitized MGMT-positive GBM cells resistant to Auranofin. NAC reverted these synergistic effects, suggesting ROS-mediated mechanism. Our study provides new insights into the modulation of the cellular redox homeostasis using sequential sunitinib and Auranofin. This will enable repurposing Auranofin and sunitinib, two drugs with a known safety profile for an effective therapeutic strategy for GBM patients.
STEM-04. CONNEXIN 43 DRIVES GLIOBLASTOMA CANCER STEM CELL PHENOTYPES THROUGH A WNK1 SIGNALING AXIS
Authors: Erin Mulkearns-Hubert, Nicole Hajdari, Justin Lathia
Journal: Neuro-Oncology (2022)

Abstract Tumors represent a highly dynamic system that relies on coordinated signaling to drive growth and adapt to selective pressures, including those induced by anti-cancer therapies. Given the need for tumors to engage in rapid and coordinated cell-cell communication, mechanisms including gap junction intracellular communication would be essential. Surprisingly, the connexin proteins that make up gap junctions have traditionally been considered tumor suppressors. This hypothesis was based on the loss of GJIC in cancer cells and, frequently, lower connexin expression in tumor cells compared to non-neoplastic tissue, including in glioblastoma (GBM), where connexin 43 (Cx43) was shown to be decreased. However, recent data suggest that this tumor-suppressive effect is context dependent and that connexins can function in a tumor-promoting role. We previously found that GBM cancer stem cells (CSCs) rely on gap junctional intercellular communication through connexin 46 (Cx46) for survival. We now identify a subset of GBM patient-derived xenograft (PDX) CSC models that also rely on Cx43 in addition to Cx46. This dependence on Cx43 is independent of Cx43 expression level. Knockdown of Cx43 using shRNA in these PDX models compromises their survival and self-renewal while inducing apoptosis. We leveraged a protein kinase phospho array to identify signaling changes associated with Cx43 knockdown and observed reductions in phosphorylation of WNK lysine-deficient protein kinase 1 (WNK1) in addition to ERK1/2, AKT, and p38MAPK. Immunoblotting validated that WNK1 phosphorylation is lost in the absence of Cx43. Treatment with a WNK1 inhibitor was toxic to CSCs. Current work is focused on interrogating the link among Cx43, WNK1 phosphorylation, and downstream signaling events and the therapeutic window of WNK1 inhibition. This work identifies a potential new signaling axis downstream of Cx43 in glioblastoma CSCs and further strengthens the hypothesis that connexins may act as both tumor suppressors and tumor drivers depending on context.
DDEL-09. FRACTIONATED INTRACAVITARY RADIOIMMUNOTHERAPY WITH LU-177 LABELED 6A10 FAB FRAGMENTS IN PATIENTS WITH GLIOBLASTOMA
Authors: Michael Müther, Wolfgang Roll, Guido Böning, Astrid Delker, Reinhard Zeidler, Franz Josef Gildehaus, Lars Stegger, Michael Schäfers, Hans-Jürgen Reulen, Walter Stummer
Journal: Neuro-Oncology (2022)

Abstract Background Radio-immunotherapy (RIT) with Lu- 177 labeled 6A10-Fab fragments, targeting tumor-associated carbonic anhydrase XII (CA12) and applied directly into the resection cavity, offers a promising strategy to address hibernating tumor burden after resection and completion of adjuvant treatment for glioblastoma. We report on the first in human applications. METHODS Three patients underwent microsurgical resection of glioblastoma. After completion of adjuvant radio- and chemotherapy, RIT was offered in a compassionate use setting. After implantation of an injection reservoir into the tumor cavity, three consecutive doses of Lu-177 labeled 6A10 Fab fragments were administered over three months, corresponding to 25% - 50% - 25% of the total activity. The injected dose was adapted to the size of the resection cavity. Dosimetry was performed with planar whole-body scintigraphy and SPECT/CT 12h, 24h, 48h, 76h and 5-7 days after injection. RESULTS Patient 1 (IDH1-Mutation) received three doses of RIT (total of 592 MBq) with stable disease 12 months after therapy and 26 months after initial diagnosis. Patient 2(IDH-Wildtype) had histologically proven tumor progression after the second cycle (total of 526 MBq). Patient 3 (IDH-Wildtype) has so far received one cycle of RIT (327 MBq of a planned total of 1300 MBq). No toxicity according to CTCAE version 6.0 or other adverse events related to RIT were observed. Dosimetry did not reveal absorbed doses above the upper dose limits for organs at risk. Conclusions Intracavitary radioimmunotherapy with Lu-177 labeled 6A10-Fab fragments appears to be a safe maintenance therapy for glioblastoma patients, albeit only assessed in three compassionate use situations far. A multicenter confirmatory phase-I-trial will be was initiated in May 2022 (EudraCT-No: 2015-004417-25) to determine the maximum tolerated dose and safety of adjuvant RIT with Lu-177 labeled 6A10-Fab fragments.
QOL-19. RETURNING TO WORK AFTER A BRAIN TUMOUR – “I THOUGHT I WOULD BE BACK AT WORK THE NEXT WEEK, HOW WRONG I WAS!”
Authors: Emma Nicklin, Isaac Phang, Susan Short, Petra Hoogendoorn, Florien Boele
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Returning to work is important for patients' and their families’ well-being, financial circumstances and quality of life. Side-effects of brain tumour (BT) treatment or clinical deterioration from BT progression often causes temporary or permanent inability to work. Aim: To explore the occupational expectations, experiences and satisfaction of BT patients (and their caregivers) following diagnosis/treatment. METHODS Qualitative semi-structured interviews were conducted with adults diagnosed with a primary BT, in employment/self-employed before diagnosis, currently in follow-up care; and their caregivers. Purposive sampling ensured a mixed BT sample. Participants were recruited from two UK tertiary referral hospitals. Data collection and thematic analysis are ongoing and will be completed by August 2022. RESULTS To date, 17 interviews (13 patient/4 caregiver) have taken place (59% female, aged 26-73,M= 43). Early findings: 1) Managing expectations: Patients underestimated the impact of surgery and how long it would take to return to work (if they had). Many would have liked more information prior to treatment about potential side-effects (e.g., extreme fatigue). 2) Prior financial support: Most patients suffered financially, often resulting in returning to work before they felt ready. Patients wanted more information prior to treatment about financial support. 3) Ongoing communication: Employers who were emotionally and practically supportive throughout the BT trajectory were highly valued. Some interviewees believed their employers needed to receive better education about BTs. 4) Flexible working: Patients returning to work with enhanced employer support (e.g., reduced hours, working from home and lighter duties) were more satisfied. 5) Better caregiver support: Many caregivers were unsupported by their employers to take carer leave, some worked more to support the family financially. CONCLUSIONS Preliminary findings offer novel data in an under-researched area. More knowledge around the experiences, barriers and facilitators influencing patients’ return to work will allow the planning of tailored occupational support and resources.
SURG-39. SURGICAL RESULTS AND LONG-TERM OUTCOME IN SUPRATENTORIAL INTRAVENTRICULAR TUMORS
Authors: Nico Teske, Mariana Chiquillo-Domínguez, Benjamin Skrap, Louisa von Baumgarten, Mathias Kunz, Joerg-Christian Tonn, Niklas Thon, Philipp Karschnia
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Intraventricular tumors (IVTs) are rare lesions of various entities, which pose a surgical challenge. We aimed to elaborate on surgical approaches and outcomes, postoperative morbidity, and elucidate whether preoperative hydrocephalus necessitates shunting despite surgical resection. METHODS We retrospectively searched the institutional database for patients with supratentorial intraventricular tumours that were treated in the Department of Neurosurgery of the Ludwig-Maximilians-University Munich, Germany between 2014 and 2022. RESULTS We identified 59 patients with supratentorial intraventricular tumors comprising over 15 different tumor entities, most often subependymoma (8/59 patients, 14%). Median age at diagnosis was 41.4 years (range 0-86 years) with 31 male patients (53%) and 28 female patients (48%). Microsurgical tumor resection was completed in 46/59 patients (78%) with incomplete tumor resection (≥ 1ml postoperative tumor volume) in 13/46 patients (28%) and complete tumor resection (&amp;lt; 1ml postoperative tumor volume) in 33/46 patients (72%). In cases where neurosurgical tumor resection was not feasible, stereotactic biopsy was provided in 13/59 patients (22%), often combined with stereotactic internal shunt implantation (5/59 patients, 8%). Mean follow-up was 24 months; median overall survival was not reached. Postoperative persistent hydrocephalus necessitating ventriculoperitoneal shunt placement was rare (5/59 patients, 8%). Ventriculocisternostomy was performed in one patient. New postoperative focal neurological deficits – mostly transient – were encountered in 16/59 patients (27%) at discharge with mild to moderate permanent focal neurological deficits at 3 months in 3/59 patients (5%). CONCLUSION Complete resection of IVT can often be achieved and forms the basis for favourable outcome. Permanent neurological deficits are rare, and hydrocephalus can almost always be alleviated which prevents the need for long-term shunting. If microsurgical resection is not feasible, stereotactic biopsy along with internal shunting represents an effective approach to establish diagnosis and ameliorate symptoms.
SURG-25. PATTERNS OF RECURRENCES ACCORDING TO THE EXTENT OF RESECTION IN PARIETNS WITH GLIOBLASTOMA, IDH-WILDTYPE: A RETROSPECTIVE STUDY
Authors: Jong Hee Chang, Jihwan Yoo, Kyung Hwan Kim, Woohyun Kim, Hong In Yoon, Se Hoon Kim, Ju Hyung Moon, Hun Ho Park, Eui Hyun Kim, Chang-Ok Suh, Seok-Gu Kang
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE In glioblastoma (GBM) patients, controlling the microenvironment around the tumor using various treatment modalities, including surgical intervention, is essential in determining the outcome of treatment. This study was conducted to elucidate whether recurrence patterns differ according to the extent of resection (EOR) and whether this difference affects prognosis. METHODS This single-center study included 358 eligible patients with histologically confirmed isocitrate dehydrogenase (IDH)-wild-type GBM from November 1, 2005, to December 31, 2018. Patients were assigned to one of three separate groups according to EOR: supratotal resection (SupTR), gross-total resection (GTR), and subtotal resection (STR) groups. The patterns of recurrence were classified as local, marginal, and distant based on the range of radiation. The relationship between EOR and recurrence pattern was statistically analyzed. RESULTS Observed tumor recurrence rates for each group were as follows: SupTR group, 63.4%; GTR group, 75.3%; and STR group, 80.5% (p = 0.072). Statistically significant differences in patterns of recurrences among groups were observed with respect to local recurrence (SupTR, 57.7%; GTR, 76.0%; STR, 82.8%; p = 0.036) and distant recurrence (SupTR, 50.0%; GTR, 30.1%; STR, 23.2%; p = 0.028). Marginal recurrence showed no statistical difference between groups. Both overall survival and progression-free survival were significantly increased in the SupTR group compared with the STR and GTR groups (p &amp;lt; 0.0001). CONCLUSIONS In this study, the authors investigated the association between EOR and patterns of recurrence in patients with IDH-wild-type GBM. The findings not only show that recurrence patterns differ according to EOR but also provide clinical evidence supporting the hypothesized mechanism by which distant recurrence occurs.
MODL-30. AN ENGINEERED TRANSGENIC MOUSE MODEL OF RETINOBLASTOMA
Authors: Xiao Liu, Yanxin Pei
Journal: Neuro-Oncology (2022)

Abstract Retinoblastoma, the most common intraocular tumor of childhood, was recently shown to comprise two major molecular subtypes. Subtype 1 includes most heritable forms, with germline mutation of RB1 and a cone-differentiated state. Subtype 2 is often non-hereditary, exhibits stemness features, increased expression of MYCN and its target genes, and a high risk of metastasis. Relative to subtype 1, subtype 2 tumors have a worse prognosis. To date, no mouse model has been available for studying subtype 2 disease. It is known that SHH pathway proteins including SHH, GLI1 and GLI2 are abnormally elevated in human retinoblastoma. We recently discovered that activation of GLI2 in the developing mouse retina leads to intraocular tumors that exhibit cellular and molecular features resembling human subtype 2 retinoblastoma with aberrant upregulation of MYCN and its target genes. Because MYCN is a downstream target of the SHH pathway, we hypothesize that inhibiting the SHH-GLI2-MYCN signaling axis may effectively treat subtype 2 disease. Using our GLI2 based mouse model of retinoblastoma, we will elucidate mechanisms underlying tumor initiation and progression, and evaluate the therapeutic potential of SHH and GLI2 inhibitors in preventing retinoblastoma. We will validate our mouse model findings using human retinoblastoma cell lines and patient-derived tumor xenografts. Our studies will yield new mechanistic insights into the development of subtype 2 retinoblastoma and identify novel molecular targets for early detection, treatment, and prevention of ocular tumors and associated metastatic disease.
BIOM-61. SYSTEMATIC REVIEW OF BIOLOGIC CORRELATES OF FRAILTY IN SOLID TUMORS: IMPLICATIONS FOR BRAIN TUMORS
Authors: Dilorom (Delia) Sass, Brennan Streck, Diane Cooper, Jennifer Guida, Terri Armstrong
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Cancer and cancer treatments contribute to accelerated aging and frailty, which is present in over 50% of adult cancer survivors and increases vulnerability to poor outcomes. Biomarkers of frailty would allow for early identification and timely interventions. The purpose of this review is to synthesize the current literature examining biomarkers of frailty across solid tumor patients, including primary brain tumors (PBT). METHODS The systematic review was conducted using preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines. PubMed, Web of Science, and Embase, were searched by the medical librarian (D.C.) of all reports from the inception to December 08, 2021. Inclusion criteria were: a) English language, b) biomarkers of aging hallmarks, c) association between biomarkers and frailty. Studies were limited to human solid tumors. Two reviewers (D.S. and B.P.S.) independently screened titles, abstracts, and full-text articles using Covidence platform with conflict resolution by the third researcher (T.S.A.). Included studies were independently evaluated for quality assessment using NIH tools for Observational Cohort, Cross-Sectional and Case-Control studies. RESULTS In total, 915 reports were screened and 15 full-text articles were included for the review. Studies were most commonly in breast tumors with no PBTs identified. Most were cross-sectional using small sample sizes. Fried, Balducci, and Leuven Oncogeriatric Frailty tools and cytokines (i.e. Interleukin-6 and C-reactive protein) were commonly used. Increased inflammatory response was the prevalent identified mechanism. Threats to internal validity of the studies were the use of unvalidated cut-off scores or modification of existing tools in about 50% of studies. Only six studies were rated as good using quality assessment ratings. CONCLUSIONS Varied use of frailty measures and nonspecific blood biomarkers limited conclusions for mechanisms of frailty in cancer survivors. There are missed opportunities in neuro-oncology; inclusion of frailty assessment and biomarkers is instrumental to advancing science in PBTs.